Photosensitized oxygenation process for preparing 20-ketosteroids from corresponding 22-enamines



United States Patent 3,468,776 PHOTOSENSI'I'IZED OXYGENATION PROCESS FOR PREPARING ZO-KETOSTEROIDS FROM CORRE- SPONDING ZZ-ENAMINES Joel E. Huber, Kalamazoo, Mich., assignor to The Upjohn Company, Kalamazoo, Micln, a corporation of Delaware No Drawing. Filed June 16, 1967, Ser. No. 646,471

Int. Cl. B011 1/10 US. Cl. 204-158 6 Claims ABSTRACT OF THE DISCLOSURE This invention relates to a single-step process'for the direct conversion, by photosensitized oxygenation, of steroid 22-enamines, i.e., steroid 20-(22)-ene-22-amines of the formula 21 CH: st-d=oH-N 1 2o 22 U I to the corresponding ZO-ketosteroids of the formula r St-C=O 11 BRIEF SUMMARY OF THE INVENTION A compresensive review of syntheses employing photosensitized oxygenation, containing numerous references, by Schenck and his co-workers appears in Agnew. Chem. 69, 579.

In carrying out the photosensitized oxygenation of the 22-enamine compounds of Formula I, photosensitizers disclosed in the Schenck article, such as hematoporphyrin, protoporphyrin, eosin Y, methylene blue, chlorophyll, hypericin, erythrocin B, chlorin E riboflavin, and rose bengal, have been found satisfactory. Advantageously, the light employed is a conventional fluorescent lamp surrounded by a glass jacket containing the steroid solution. Such an arrangement can be modified and adapted to provide a continuous flow process for large scale conversions; e.g., in vessels of large volume, irradiation can be accomplished by inserting the fluorescent lamp into glass wells or positioning them against glass ports. However, the process of the invention is not limited to the use of this particular light source. Thus, any light source producing radiation in the region of maximum absorption of the photosensitizer can be used. Sun light can also be used for this purpose, as well as incandescent lamps and carbon arc lights.

The preferred solvents are acetone, pyridine, methylene chloride, ethyl acetate, and dimethylformamide. Inert solvents such as benzene and ethanol can also be used.

The optimum temperature for the photosensitized oxygenation of the starting steroid 22-enamines 1) was found to be between about 0 C. to about 40 C., but temperatures between about l00 C. and about 80 C. are also satisfactory.

The time required for conversion of the compounds of Formula I to the corresponding ZO-ketones (II) by the photosensitized oxygenation reaction depends on such factors as, light intensity, the rate of oxygen bubbling through the reaction mixture, the amount of photosensitizer present and the amount of substrate (I). Oxygen is "ice usually bubbled through the reaction mixture throughout the course of the conversion; air can also be used. Pressure vessels charged with oxygen and illuminated either from within or through glass ports can also be used. The progress of the reaction is followed by taking aliquots for thin-layer chromatography and terminating the reaction when the starting material (I) is converted to the 20- ketone (II).

All of the compounds embraced by Formula II can be isolated from their reaction mixtures by conventional means, for example, when a water-miscible solvent is used, by pouring the reaction mixture into water and separating the resulting precipitate by filtration or by extraction with water-immiscible solvents. Additional purification of the product can be accomplished by conventional means, for example, by elution chromatography from an adsorbent colunm with a suitable solvent such as acetone, methanol, dilute methanol, ethanol, ether, methylene chloride and Skellysolve B (hexanes), mixtures and combinations of these solvents; also by gradient elution chromatography from an adsorbent column with a suitable mixture of solvents, such as methylene chloride- Skellysolve B, acetone-Skellysolve B, and the like.

The steroid ZZ-enamines (I) employed as starting materials in the process of the present invention are prepared in accordance with the procedures described in J. Amer. Chem Soc. 85, 207 and U.S. Patent 2,752,337, namely, by the reaction of a corresponding steroid 22-aldehyde with a. secondary amine. The 22-aldehydes are prepared in the manner set forth in J. Amer. Chem. Soc. 80, 915, 69, 1957 and 70, 2953. Representative steroid 22-aldehydes which can be converted to their corresponding 22-amines (I) include bisnorcholan-ZZ-al, 3,8-acetoxybisnorcholan- 22-al, 3fl-benzoxybisnorcholan-22-al, 3t? alphanapthoxybisnorcholan-ZZ-al, 3fl-methoxybisnorcholan-22-al, 3 8- benzyloxybisnorcholan 22 al, 3B-hydroxybisnorcholan- 22-al, 3-ketobisnorcholan-22-al, 3fl-acetoxybisnor-5- cholen-22-al, 3 8-n-butyroxybisnor-S-cholen-ZZ-al, 35- phenylacetoxybisnor-S-cholen-22-al, 3fl-isopr0pyl0xybisnor-5-cholen-22-al, 3B'hydroxybisnor-5-cholen-22-al and the i steroids thereof, 3-ketobisnor-4-cholen-22-al, the maleic anhydride, maleimide, and maleic ester adducts of bisnor-5,7choladien-22-al, 3,B-acetoxybisnor-SJ-choladien-ZZ-al, 3B-benzoxybisnor-S,7-choladien-22-al, 3 3- ethoxybisnor-5,7-choladien-22-al, 3/i-triphenylmethoxybisnor-5,7-choladien-22-al, 3B-hydroxybisnor-SJ-choladien-22-al, 3-ketobisnor-5,7-choladien-22-al, bisnor- 5,7,9-cholatrien-22-al, 3fl-propionoxybisnor-S,7,9-ch0- latrien 22 al, 3B-benzyloxybisnor-5,7,9-cholatrien-22-al, 3B-hydr0xybisn0r-5J,9-ch0latrien-22-al, 3-ketobisnor- 5,7,9-cholatrien-22-al, 3;8-acetoxy-9,11-oxidobisnor-5,7- choladien-ZZ-al, 3 ,B-n-hexyloxy-9, l l-oxidobisnor-5,7-choladien 22 al, 35 hydroxy-9,ll-oxidobisnor-5,7-choladien-22-al, 3-keto-9, l l-oxidobisnor-5,7-choladien-22-al, and the like. The foregoing and similar steroid 22-aldehydes which can be reacted with secondary amines can be prepared by methods heretofore described in the art. The preparation of the 3p-hydroxy, 3fl-acetoxy, 35- methoxy, 3,8-benzy1oxy and the i-methyl ether bisnor-S- cholen-22-als are described in J. Amer. Chem. Soc. 69, 1957 and 70, 2953. 3-keto-bisnor-4-cho1en-22-al and a method for its preparation is described in J. Amer. Chem. Soc. 80, 915. The maleic anhydride adducts of 3,8-acetoxybisnor-5-7-choladien-22-al and 3B-acetoxy-9,ll-oxidobisnor-5,7-choladiene-22-al and methods for their preparation are described in J. Org. Chem. 13, 10-20 and adducts of 3-ketobisnor-5,7,9-(ll)-cholatrien-22-al and methods for their preparation are described in U.S. Patent 2,530,389.

Additional steroid 22-aldehydes, e.g., 3,6,5a-dioxygenated-ll-keto-9/3-bisnorcholan-22-als and their corresponding 9 8,l1p-epoxides, can be prepared in the manner disclosed in US. Patent 2,897,213. Numerous 22-aldehydes can be prepared from the compounds embraced by the generic formula designated (a) in column 4 of US. Patent 3,281,415 by employing the procedures of Example IV of US. Patent 3,022,324; in those compounds of Formula (A) wherein Y is C=O, the procedure of Example IV is modified by first forming a 3-ketal protective group and, following the formation of the 22-al radical, restoring the 3-keto function by acid hydrolysis of the 3-ketal.

Representative secondary amines which can be em- I ployed in the preparation of steroid enamines (I) from corresponding steroid 22-aldehydes include dialkylamines such as diethylamine, dibutylamine, dioctylamine, and didodecylamine; cycloalkylamines such as dicyclohexylamine and the like, cyclic amines such as piperidine, pyrrolidine, tetrahydroquinoline, oxazolidine (tetrahydrooxazole), morpholine and the like; aralkylalkyl amines such as N-methylbenzylamine, dibenzylamine and the like; substituted dialkylamines such as diethanolamine and the like; and arylalkylamines such as N-methylaniline, N-methyltoluidine, N-methylanisidine, and the like. However, it is preferred, for convenience and economy, to use secondary amines whose molecular weights are between approximately 70 and approximately 150, such as pyrrolidine, piperidine, morpholine and diethylamine.

The compounds prepared by the process of this invention embraced by Formula II possesses valuable pharmacological properties, particularly 1) anti-inflammatory and (2) progestational activities. These properties render them useful in (1) the treatment of various inflammatory conditions of the skin, eyes, respiratory tract, bones and internal organs due to viral or bacterial infections, contact dermatitis, allergic reactions and rheumatoid arthritis, and in (2) the maintenance of pregnancy. The compounds of the aforesaid formula are also useful as intermediates in the preparation of a wide variety of physiologically highly active and therapeutically valuable (1) anti-inflammatory and (2) progestational compounds.

DETAILED DESCRIPTION It is to be understood that the invention is not to be limited to the exact details of operation or exact compositions shown and described herein, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

PREPARATION 1 22-(N-morph olinyl) -bisnr-4,20 (22 -ch0ladien-3-0ne (I) A mixture of 6.57 g. of barium oxide, 6.57 g. of 3-ketobisnor-4-cholen-22-al (prepared as described in J. Amer. Chem. Soc. 72, 2617), 1.92 ml. of morpholine and 100 ml. of benzene was stirred for about minutes at room temperature in an atmosphere of nitrogen and then heated under reflux for about 2.75 hours with continued stirring. The mixture was then cooled, filtered and the filter cake washed with about ml. of benzene. The organic filtrates were then combined and the solvents removed by distillation at reduced pressure to give 8.19 g. of crude material, which on trituration with about 24 ml. of cold acetone yielded 6.66 g. of 22-(N-morpholiny1)-bisnor-4,20(22)- choladien-3-one (I), melting at 155 to 160 C.

Analysis.Calcd for C H O N: C, 78.7; H, 9.89; N, 3.52. Found: C, 79.0; H, 9.70; N, 3.58.

PREPARATION 2 22-(N-piperidinyl) -bisnor-4,20(22)-choladien-3-0ne (I) To a solution of 41 g. of 3-ketobisnor-4-cholen-22-al (prepared as described in J. Amer. Chem. Soc. 74, 3627) in 600 ml. of benzene, 15 ml. of piperidine was added and the mixture heated at brisk reflux under an atmosphere of nitrogen using a moisture trap to collect the water of reaction. After about 3 hours the calculated amount of water had collected in the trap; the reaction mixture was taken to dryness in vacuo on a hot Water-bath and the residue placed in a dessicator under reduced pressure over phosphrous pentoxide for about 72 hours. The residue was thoroughly agitated with about 150 ml. of methanol, the methanolic extract cooled to about 4 C. for about 3.5 hours, filtered, and the filter cake washed with about 10 ml. of cold methanol and dried to obtain an 86% yield of 22-(N-piperidinyl)-bisnor-4,20(22)-choladien 3 one (I) melting at 128 to 133 C. (dec); [a]

Analysis.Calcd for C27H41ON1 C, 81.98; H, 10.45; N, 3.54. Found: C, 81.92; H, 10.45; N, 3.52.

The following 22-enamines can be prepared in manners essentially as described in Preparations 1 and 2:

(1) 22-diethylaminobisnor-20(22)-cholene (I) by heating bisnorcholan-22-al with a slight excess of diethylamine,

(2) 3fl-acetoxy-22 di-n-butylaminobisnor 20(22)- cholene (I) by heating 3fi-acetoxybisnorcholan-ZZ-al with a slight excess of di-n-butylamine,

(3) 3 3-benz0xy-22-dioctylaminobiSn0r-20( 22) -cholene (I) by heating 3B-benzoxybisnorcholan-22-a1 with a slight excess of dioctylamine,

(4) 3,8-alpha naphthoxy-22-didodecylaminobisnor-20 (22)-cholene (I) by heating 3fi-alpha-naphthoxybisnorcholan-22-al with a slight excess of didodecylamine,

(5) 3B methoxy-22dicyclohexylaminobisnor-20(22)- cholene (I) by heating 3B-methoxybisnorcholan-22-al with a slight excess of dicyclohexylamine,

(6) 3,6 benzyloxy-22-piperidinobisnor-20(22)-cholene (I) by heating 35-benzyloxybisnorcholan-22-al with a slight excess of piperidine,

(7) 3B hydroxy 22-pyrrolidinobisnor-20(22)-cholene (I) by heating 3,B-hydroxybisnorcholan-22-al with a slight excess of pyrrolidine,

(8) 3 keto-22-tetrahydroquinolinobisnor-ZO(22)-cholene (I) by heating 3-ketobisnorcholan-22-al with a sli excess of tetrahydroquinoline,

(9) 3B n butyroxy 22 oxazolidinobisnor 5,20- (22) choladiene(I) by heating 3B n butyroxybisnor-5- cholen 22 yr al with a slight excess of oxadine,

(10) 3B phenylacetoxy 22 morpholinobisnor 5- 20(22) choladiene (I) by heating 35 phenylacetoxybisnor-5-cholen-22-al with a slight excess of morpholine,

(11) 313 isopropyloxy 22 N methylbenzylaminobisnor-5,20(22)-choladiene (I) by heating 3/3-isopropyloXybisnor-5-eholen22-al with a slight excess of N-methylbenzylamine,

(12) The dimethyl maleate adduct of 22-dibenzylaminobisnor-5,7,20(22)-cholatriene (I) by heating the dimethyl maleate adduct of bisnor-5,7-choladien-22-al with a slight excess of dibenzylamine,

(13) The maleic anhydride, adduct of 3fi-acetoxy-22- diethanolaminobisnor-5,7,20(22)-cholatriene (I) by heating the maleic anhydride adduct of 3B-acetoxybisnor-5,7- choladien-22-al with a slight excess of diethanolamine,

(14) The diethyl maleate adduct of 3B-benzoxy-22-(2- methyl-pyrrolidino)-bisnor-5,7,20(22)-cholatriene (I) by heating the diethyl maleate adduct of 3B-benzoxybisnor- 5,7-choladien-22-al with a slight excess of Z-methylpyrolidine,

(15) The di-n-butyl maleate adduct of 3fi-ethoxy-22- (2-methylpiperidino)-bisnor-5,7,20(22)-cholatriene (I) by heating the di-n-butyl maleate adduct of SB-ethoxybisnor- 5,7-choladien-22-al with a slight excess of Z-methylpiperidine,

(16) the dibenzyl maleate adduct of 3,8-triphenylmethoxy 22 (3 methylpiperidino) bisnor 5,7,20(22)- cholatriene (I) by heating 3fi triphenylmethoxybisnor- 5,7-choladien-22-al with a slight excess of 3-methylpiperidine,

(17) The maleimide adduct of 3/8-hydroxy-22-oxazolidinobisnor-5,7,20(22)-cholatriene (I) by heating the maleimide adduct of 3 B-hydroxybisnor-S,7-choladien-22-al with a slight excess of oxazolidine,

(18) The maleic anhydride adduct of 3-keto-22-Inorpholinobisnor-5,7,20(22)-cholatriene (I) by heating the maleic anhydride adduct of 3-ketobisnor-5,7-choladien- 22-al with a slight excess of morpholine,

(19) The dimethyl maleate adduct of 35-propionoxy- 2 2-piperidinobisnor-5,7,9,20(22)-cholatetraene (I) by heating the dimethyl maleate adduct of 35-propionoxybisnor-5,7,9-cholatrien-22-al with a slight excess of piperidine,

(20) The maleic anhydride adduct of 3-keto-22-(2- methylpyrrolidino)-bisnor-5,7,9,20(22)-cholatetraene (I) by heating the maleic anhydride adduct of 3-ketobisnor- 5,7,9-cholatrien-22-al with a slight excess of Z-methylpyrrolidine,

(21) The dimethyl maleate adduct of 35acetoxy-9,11- oxido 22 N methylanilinobisnor 5,7,20(22) cholatriene (I) by heating the dimethyl maleate adduct of 35 acetoxy 9,11 oxidobisnor 5,7 choladien 22 2.1 with a slight excess of N-methylaniline,

(22) 35 hydroxy 22 N methylanisidinobisnor- 5,7,9,20(22)-cholatetraene (I) by heating 3-hydroxybisnor 5,7,9,20(22) cholatetraene (I) by heating 35- hydroxybisnor-S,7,9-cholatrien-22-al with a slight excess of N-methylanisidine,

(23) The dimethyl maleate adduct of 3 5,125-diacetoxy- 22 morpholinobisnor 5,7,9,20(22) cholatetraene (I) by heating the dimethyl maleate adduct of 35-125-diacetoxybisnor-5,7,9-cholatrien-22-al with a slight excess of morpholine,

(24) 22 (N morpholinyl) 35,5a dihydroxy 11- keto-95-bisnor-20(22)-cholen (I) by heating 35,5a-dihydroxy 11 keto 95 bisnor cholan 22 al with a slight excess of morpholine,

(25) 22 (N piperidinyl) 35 acetoxy 5a hydroxy 95,115 oxido bisnor 20(22) cholen (I) by heating 35 acetoxy 5a hydroxy 95,115 oxidobisnorcholan 22 al with a slight excess of piperidine,

(26) (N dibenzylaminyl) 3 ketobisnor -'1,4,- 20(22)-cholatriene (I) by heating 3-ketobisnor-1,4-cho1adien-22-al with a slight excess of dibenzylamine,

(27) 22 (N morpholinyl) 3 ketobisnor 4,6, 20- (22)-choladiene (I) by heating 3-ketobisnor-4,6-choladien-22-al with a slight excess of morpholine,

(28) 22 (N diethylaminyl) 3 ketobisnor 4,7- 20(22) cholatriene (I) by heating 3 ketobisnor 4,7- choladien-22-al with a slight excess of diethylamine,

(29) 22 (N pyrrolidinyl) 3 ketobisnor 2ozmethyl 4,20(22) choladiene (I) by heating 3-ketobisnor 2a methyl 4 choladen 22 al with a slight excess of pyrrolidine,

(30) 22 (N 2 methylpyrrolidinyl) 3 ketobisnor- 6u methyl 1,4,20(22) cholatriene (I) by heating 3 ketobisnor 6oz methyl 1,4 choladien 22 a1 with a slight excess of Z-methylpyrrolidine,

(31) 22 (N methylanilinyl) 3 ketobisnor 7amethyl 4,20(22) choladiene (I) by heating 3 ketobisnor 7oz methyl 4 cholen 22 al with a slight excess of methylaniline,

(32) 22 (N anisidinyl) 35,110: dihydroxy bisnor 20(22) cholene (I) by heating 35,110; dihydroxy bisnorcholan 22 al with a slight excess of anisidine,

(33) 22 (N tetrahydroquinolinyl) 3 ethylenedioxy 6a fluoro 115 hydroxy bisnor 20(22) cholene (I) by heating 3 ethylenedioxy 60c fluoro 115- hydroxy-bisnorcholan-ZZ-al with a slight excess of tetrahydroquinoline,

(34) 22 (N morpholinyl) 3 ethylenedioxy 5ahydroxy 65 fluoro 11 keto bisnor 20(22) cholene (I) by heating 3-ethylene-dioxy-5u-hydroxy-65-fluoro-11- keto-bisnorcholan-ZZ-al with a slight excess of morpholine,

(35) 22 (N dioctylaminyl) 3 ketobisnor 9afluoro 115 hydroxy 4,20(22) choladiene (I) by heating 3 ketobisnor 9a fluoro 115 hydroxy 4- cholen 22 al with a slight excess of dioctylamine,

(36) 22 (N piperidinyl) 3 ketobisnor 6a,90zdifluoro 115 hydroxy 6oz methyl 1,4,20(22) cho- 6 latriene (I) by heating 3 ketobisnor 60:,90: difluoro- 115 hydroxy 6a methyl 1,4 choladiene with a slight excess of piperidine,

(37) 22 (N dicyclohexylaminyl) 3 ketobisnor- 6o: methyl 115 hydroxy 4,20(22) choladiene (I) by heating 3 ketobisnor 60c methyl 115 hydroxy- 4 cholen 22 al with a slight excess of dicyclohexylamine.

(38) 22 (N morpholinyl) 3 ketobisnor 901,115- dichloro 4,6,20(22) cholatriene (I) by heating 3- ketobisnor dichloro 4,6 choladien 22 al with a slight excess of morpholine,

(39) 22 (N piperidinyl) 3 ketobisnor 115 hydroxy 1,4,6,20(22) cholatetraene (I) by heating 3- ketobisnor 115 hydroxy 1,4,6 cholatrien 22 al with a slight excess of piperidine, and

(40) 22 (N morpholinyl) 3 ketobisnor 6a,- methyl 9oz cholo 115 hydroxy 1,4,20(22) cholatriene (I) by heating 3 ketobisnor 6oz methyl 9achloro 115 hydroxy 1,4 choladien 22 al with a slight excess of morpholine.

EXAMPLE 1 Preparation of 4-pregnene-3,20-dione (II) by the photosensitized oxygenation of ZZ-(N-morphonlinyl)bisnor- 4,20(22)-choladien-3- one (I) A slurry of 5 g. 12.6 mmoles) of 22-(N-morpholinyl)- bisnor-4,20(22)-choladien-3-one (I), 20 mg. of rose bengal dye and 25 ml. of dimethylformide were placed in a 2.5 cm. x 56 cm. glass tube fitted with a medium porosity fritted disk at the bottom and a cold finger mounted at the top which extended through the center of the tube to the fritted disk. Oxygen was passed through the disk at a rate of 0.25 cu. ft./hour while the tube was illuminated with four 15 watt fluorescent lamps. This temperature was maintained at about 15 C. throughout the reaction period of about 17.5 hours. The reaction mixture was then drained from the tube and about g. of crushed ice was added portionwise with stirring over a period of about 1 hour. This mixture was stored at about 0 C. for about 4 hours and then the solids therein collected by filtration, washed with water and dried under vacuum to constant weight to alIord a quantitative yield (3.96 g.) of 4-pregnene-3,20-dione, also known as progesterone (H), melting at 126 to 128 C., [u] +175.6 (dioxane).

In a manner essentially as described in Example 1, the following 20-ketosteroids (II) can be prepared by the photosensitized oxygenation of the corresponding 22-enamines (I), as follows:

(1) pregnan 20 one (II) from 22 diethylaminobisnor 20(22) cholene (I),

(2) 35 acetoxy pregnan 20 one (H) from 35- acetoxy 22 di n butylaminobisnor 20(22) cholene (3) 35 methoxy pregnan 20 one (II) from 35- methoxy 22 dicyclohexylaminobisnor 20(22) cholene (I),

(4) 3a hydroxy pregnan 20 one (II) from 30:- hydroxy 22 pyrrolidinobisnor 20(22) cholene (I),

(5) pregnan 3,20 dione (II) from 3 keto 22- tetrahydro quinolinobisnor 20(22) cholene (I),

(6) 35 butyroxy 5 pregnen 20 one (II) from 35 butyroxy 22 oxazolidinobisnor 5,20(22) choladiene (I),

(7) 35 isopropoxy 5 pregnen 20 one (II) from 35 isopropoxy 22 N methylbenzylaminobisnor 5,- 20(22)-choladiene (I),

(8) the dimethyl maleate adduct of 5,7-pregnadien-20- one (II) from the dimethyl maleate adduct of 22-dibenzylaminobisnor-5,7,2O (22 -cholatriene (I) (9) the maleic anhydride adduct of 35-acetoxy-5,7 pregnadiene-3,20-dione (II) from the maleic anhydride adduct of 35 acetoxy 22 diethanolaminobisnor 5,- 7,20(22) cholatriene (I),

(10) the maleic anhydride adduct of 5,7-pregnadien- 3,20-dione (II) from the maleic anhydride adduct of 3 keto 22 morpholinobisnor 5,7,20 (22) cholatriene (11) the dimethyl maleate adduct of 35-propionoxy- 5,7,9-pregnatrien-20-one (II) from the dimethyl maleate adduct of 35 propionoxy 5,7,9,20(22) cholatetraene (12) the dimethyl maleate adduct of 35-acet0xy-9,11- oxide-5,7-pregnadien-20-one (II) from the dimethyl male- -ate adduct of 35 acetoxy 9,11 oXido 22 N methylanilinobisnor-S ,7 ,20 (22 -cholatriene (I (13) 1,4 pregnadiene 3,20 dione (II) from 22- (N methylanilinyl) 3 ketobisnor 1,4,20(22) cholatriene (I),

(14) 4,6 pregnadiene 3,20 dione (II) from 22- (N 2 methyl pyrrolidinyl) 3 ketobisnor 4,6,20- (22)-cholatriene (I),

(15) 4,7 pregnadiene 3,20 dione (II) from 22- (N oxazolidinyl) 3 ketobisnor 4,7,20(22) cholatriene (I),

(16) 4oz methyl 4 pregnene 3,20 dione (II) from 22 (N dibenzyl arninyl) 3 ketobisnor 4ozmethyl 4,20(22) choladiene (I),

(17) Zcc,6cz dimethyl 4 pregnene 3,20 dione (II) from 22 (N pyrrolidinyl) 3 ketobisnor 2a,6a dimethyl 4,20(22) choladiene (I),

(18) 7a methyl 4 pregnene 3,20 dione (II) from 22 (N dibenzyl aminyl) 3 ketobisnor 7amethyl 4,20(22) choladiene (I),

(19) 35,111: dihydroxy pregnan 20 one (II) from 22 (N dicyclohexylaminyl) 35, 11a dihydroxy bisnor 20(22) cholene (I),

(20) 3 propylenedioxy 60:, chloro 115 hydroxypregnan 20 one (II) from 22 (N-piperidinyl) 3- propylenedioxy 6a chloro 115 hydroxy bisnor '20- (22)-cholene (I),

(21) 3 ethylenedioxy a,115 dihydroxy 65- fluoro pregnan 20 one (11) from 22 (N dioctylaminyl) ethylenedioxy 50:,115 dihydroxy 65 fluorobisnor 20(22) cholene (I),

(22) 9a fluoro 115 hydroxy 4 pregnene 3,20 dione (II) from 22 (N tetrahydroquinolinyl) 3- ketobisnor 9a fluoro 115 hydroxy 4,20(22) choladiene (I),

(23) 911,115 dichloro 1,4 pregnadiene 3,20 dione (II) from 22 (N anisidinyl) 3 ketobisnor 90:,115- dichloro 1,4,20(22)-cholatriene (I),

(24) 115 hydroxy 1,4,6 pregnatriene 3,20 dione (II) from 22 (N morpholinyl) 3 ketobisnor 115- hydroxy 1,4,6,20(22) cholatetraene (I),

(25) 6oz methyl c fluoro hydroxy 1,4- pregnadiene 3,20 dione (II) from 22 diethanolaminobisnor 6a methyl 9a fluoro 115 hydroxyl,4,20(22) cholatriene (I).

(26) 3a,11a diacetoxy pregnan 20 one (II) from 22 dicyclo heptylaminobisnor 3a,11a diacetoxy- 20(22) cholene (I),

(27) 35,115 dihydroxy 5 pregnen 20 one (II) from 22 (2 methylpyrrolidinyl) 35,115 dihydroxy- 5,20(22) choladiene (I),

(28) 35 acetoXy 9(11) pregnen 20 one (II) from 22 (N methylanisidinyl) 35 acetoxy 9(11), 20(22) choladiene (I),

(29) 3 (2,2' dimethylpropylidenedioxy) 65 methyl 50:,115 dihydroxy pregnan 2O one (II) from 22 (N morpholinyl) 3 (2,2' dimethylpropylidenedioxy) 65 methyl 511,115 dihydroxy 20(22) cholene (I) and (30) 3a naphthoxy 11oz hydroxy pregnan 20- one (II) from 22(N piperidinyl) 30c naphthoxy- 11a hydroxy 20(22) cholene (I).

I claim:

1. A process for production of a 20-ketosteroid which comprises: subjecting a corresponding steroid 22-enarnine to photosensitized oxygenation.

2. A process in accordance with claim 1 wherein the starting material is a 22-enarnine of 3-ketobisnor-4-cholen- 22-211 and the product is 4-pregnene-3,20-dione.

3. A process in accordance with claim 1 wherein the starting material is a 22-enamine of 3-ketobisnor-1,4- cho1adien-22-al and the product is 1,4-pregnadien-3,20- dione.

4. A process in accordance with claim 1 wherein the starting material is a 22-enamine of 3-ketobisnor-4,6- choladien-22-al and the product is 4,6-pregnadien-3,20- dione.

5. A process in accordance with claim 1 wherein the starting material is a 22-enamine of 3-ketobisnor-4,7- choladien-22-al and the product is 4,7-pregnadien-3,ZO-dione.

6. A process in accordance with claim 1 wherein the starting material is 22-(N-morpholinyl)-bisnor-4,20(22)- choladien-3-one and the product is 4-pregnene-3,20-dione.

References Cited UNITED STATES PATENTS 3,038,909 6/1962 Kerwin 204-l58 X 3,352,920 11/1967 Meinwald 204-158 X HOWARD S. WILLIAMS, Primary Examiner 

